RESUMO
The discovery and optimization of a novel series of G9a/GLP (EHMT2/1) inhibitors are described. Starting from known G9a/GLP inhibitor 5, efforts to explore the structure-activity relationship and optimize drug properties led to a novel compound 13, the side chain of which was converted to tetrahydroazepine. Compound 13 showed increased G9a/GLP inhibitory activity compared with compound 5. In addition, compound 13 exhibited improved human ether-a-go-go related gene (hERG) inhibitory activity over compound 5 and also improved pharmacokinetic profile in mice (oral bioavailability: 17 to 40%). Finally, the co-crystal structure of G9a in complex with compound 13 provides the basis for the further development of tetrahydroazepine-based G9a/GLP inhibitors.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A highly stereoselective synthesis of the racemic oxatetracyclic core of platensimycin has been accomplished from a known bicyclic epoxy lactone by an 11-step sequence that involves a Diels-Alder cyclcoaddition to construct its cis-decalenone structural motif with complete regio- and stereoselectivity and a ring-closing metathesis to establish its whole carbon framework.
Assuntos
Adamantano/química , Adamantano/síntese química , Aminobenzoatos/química , Aminobenzoatos/síntese química , Anilidas/química , Anilidas/síntese química , Compostos Policíclicos/química , Compostos Policíclicos/síntese química , Ciclização , Reação de Cicloadição , Estrutura Molecular , EstereoisomerismoRESUMO
Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating ß-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating ß-thalassemia and sickle cell disease.
RESUMO
The first synthesis of (-)-isishippuric acid A was accomplished in two steps from a bicyclic synthetic intermediate for isishippuric acid B, which confirmed the structure of isishippuric acid A, including its absolute stereochemistry.
Assuntos
Antozoários/química , Hidrocarbonetos Aromáticos com Pontes/síntese química , Ácidos Dicarboxílicos/síntese química , Animais , Hidrocarbonetos Aromáticos com Pontes/química , Ácidos Dicarboxílicos/química , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
The first enantioselective total synthesis of isishippuric acid B bearing a novel 4,5-seco-6-norquadrane skeleton was accomplished from (R)-citronellal with use of a Diels-Alder cycloaddition and an intramolecular Michael addition as the ring-forming steps. Comparison of the optical rotation of the synthetic material with that of the natural product confirmed the absolute configuration of isishippuric acid B to be 1R, 2R, 8R, and 11R.